The present invention relates to new substituted cyclic compounds having very valuable pharmacological characteristics in respect of melatoninergic receptors.
The prior art discloses retroamide chain indoles substituted by amides or carbamates for use as antagonists of GnRH (WO 9721707) and amide chain indoles substituted by amides, carbamates or ureas for use as antihypertensive agents (U.S. Pat. No. 4,803,218).
Retroamide chain benzofuran and benzothiophene compounds substituted by amides or carbamates have also been described as anti-inflammatory agents (EP 685475) or inhibitors of bone resorption.
In the last ten years, numerous studies have demonstrated the major role played by melatonin (5-methoxy-N-acetyltryptamine) in numerous physiopathological phenomena and also in the control of circadian rhythm. Its half-life is, however, quite short owing to its being rapidly metabolised. It is thus very useful to be able to provide the clinician with melatonin analogues that are metabolically more stable and that have an agonist or antagonist character on the basis of which a therapeutic effect that is superior to that of the hormone itself may be expected. In addition to their beneficial action on disorders of circadian rhythm (J. Neurosurg. 1985, 63, pp 321-341) and sleep disorders (Psychopharmacology, 1990, 100, pp 222-226), ligands of the melatoninergic system have valuable pharmacological properties in respect of the central nervous system, especially anxiolytic and antipsychotic properties (Neuropharmacology of Pineal Secretions, 1990, 8 (3-4), pp 264-272) and analgesic properties (Pharmacopsychiat., 1987, 20, pp 222-223), and also for the treatment of Parkinson""s disease (J. Neurosurg. 1985, 63, pp 321-341) and Alzheimer""s disease (Brain Research, 1990, 528, pp 170-174). Those compounds have also shown activity on certain cancers (Melatoninxe2x80x94Clinical Perspectives, Oxford University Press, 1988, pp 164-165), ovulation (Science 1987, 227, pp 714-720), diabetes (Clinical Endocrinology, 1986, 24, pp 359-364), and in the treatment of obesity (International Journal of Eating Disorders, 1996, 20 (4), pp 443-446). Those various effects take place via the intermediary of specific melatonin receptors. Molecular biology studies have shown the existence of a number of receptor sub-types that can bind the hormone (Trends Pharmacol. Sci., 1995, 16, p 50; WO 97.04094). It has been possible to locate some of those receptors and to characterise them for different species, including mammals. In order to be able to understand the physiological functions of those receptors better, it is very valuable to have specific ligands available. Moreover, by interacting selectively with one or other of those receptors, such compounds can be excellent medicaments for the clinician in the treatment of pathologies associated with the melatoninergic system, some of which have been mentioned above.
In addition to the fact that the compounds of the present invention are new, they exhibit very great affinity for melatonin receptors and/or selectivity for one or other of the melatoninergic receptor sub-types.
More specifically, the present invention relates to compounds of formula (I):
Rxe2x80x94Axe2x80x94Rxe2x80x2xe2x80x83xe2x80x83(I)
wherein
A represents:
a ring system of formula (II): 
xe2x80x83wherein
X represents an oxygen, sulphur or nitrogen atom or a group C(H)q (wherein q is 0, 1 or 2) or NR0 (wherein R0 represents a hydrogen atom, a linear or branched (C1-C6)alkyl group, an aryl group, an aryl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched, or SO2Ph),
Y represents a nitrogen atom or a group C(H)q (wherein q is 0, 1 or 2),
Z represents a nitrogen atom or a group C(H)q (wherein q is 0, 1 or 2), but X, Y and Z cannot represent three hetero atoms simultaneously,
B represents a benzene or pyridine nucleus,
the symbol . . . means that the bonds may be single or double, it being understood that the valency of the atoms is respected,
wherein R substitutes the ring B and Rxe2x80x2 substitutes the ring containing the groups X, Y and Z, or R and Rxe2x80x2 substitute the ring B,
a ring system of formula (III): 
xe2x80x83wherein
Xxe2x80x2 represents an oxygen or sulphur atom or a group C(H)q (wherein q is 0, 1 or 2),
Yxe2x80x2 represents a group C(H)q (wherein q is 0, 1 or 2) or NR0 wherein R0 is as defined hereinbefore,
Zxe2x80x2 represents a group C(H)q (wherein q is 0, 1 or 2) or NR0 wherein R0 is as defined hereinbefore,
Txe2x80x2 represents an oxygen or sulphur atom or a group C(H)q (wherein q is 0, 1 or 2),
it being understood that, when Yxe2x80x2 or Zxe2x80x2 represents a hetero atom, the other three variables ((Xxe2x80x2, Zxe2x80x2, Txe2x80x2) and (Xxe2x80x2, Yxe2x80x2, Txe2x80x2), respectively) cannot represent a hetero atom,
the symbol . . . is as defined hereinbefore,
Bxe2x80x2 represents:
a benzene nucleus,
a naphthalene nucleus when Xxe2x80x2, Yxe2x80x2, Zxe2x80x2 and Txe2x80x2 do not simultaneously represent a group C(H)q (wherein q is 0, 1 or 2),
or a pyridine nucleus when Xxe2x80x2 and Txe2x80x2 simultaneously represent a group C(H)q (wherein q is 0, 1 or 2),
wherein R substitutes the ring Bxe2x80x2 and Rxe2x80x2 substitutes the ring containing the groups Xxe2x80x2, Yxe2x80x2, Zxe2x80x2 and Txe2x80x2, or R and Rxe2x80x2 substitute the ring Bxe2x80x2,
a ring system of formula (IV): 
xe2x80x83representing the ring systems (IVa-d): 
xe2x80x83wherein
n is an integer such that 0xe2x89xa6nxe2x89xa63,
W represents an oxygen, sulphur or nitrogen atom, or a group [C(H)q]p (wherein q is 0, 1 or 2, and p is 1 or 2) or NR0 wherein R0 is as defined hereinbefore,
the symbol . . . is as defined hereinbefore,
wherein Rxe2x80x2 substitutes the ring 
xe2x80x83and R substitutes one or other of the two other rings,
or a biphenyl group wherein R substitutes one of the benzene rings and Rxe2x80x2 substitutes the other, or R and Rxe2x80x2 substitute the same benzene ring,
it being understood that the ring systems of formulae (II), (III) and (IV) and the biphenyl group may be unsubstituted or substituted (in addition to the substituents R and Rxe2x80x2) by from 1 to 6 radicals, which may be the same or different, selected from Ra, ORa, CORa, COORa, OCORa, OSO2CF3 and halogen atoms,
wherein Ra represents a hydrogen atom, an unsubstituted or substituted linear or branched (C1-C6)alkyl group, an unsubstituted or substituted linear or branched (C2-C6)alkenyl group, an unsubstituted or substituted linear or branched (C2-C6)alkynyl group, a linear or branched (C1-C6)polyhaloalkyl group, an unsubstituted or substituted (C3-C8)cycloalkyl group, an unsubstituted or substituted (C3-C8)cycloalkyl-(C1-C6)alkyl group in which the alkyl group is linear or branched, an unsubstituted or substituted (C3-C8)cycloalkenyl group, an unsubstituted or substituted (C3-C8)cycloalkenyl-(C1-C6)alkyl group in which the alkyl group is linear or branched, an aryl group, an aryl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched, an aryl-(C1-C6)alkenyl group in which the alkenyl moiety is linear or branched, a heteroaryl group, a heteroaryl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched, a heteroaryl-(C1-C6)alkenyl group in which the alkenyl moiety is linear or branched, an unsubstituted or substituted linear or branched (C1-C6)heterocycloalkyl group, an unsubstituted or substituted heterocycloalkenyl group, a substituted or unsubstituted heterocycloalkyl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched, or a substituted or unsubstituted heterocycloalkenyl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched,
R represents:
a group of formula (V): 
xe2x80x83wherein
Q represents a sulphur or oxygen atom,
R1 represents a group NRxe2x80x2aRxe2x80x3a or OR1a (wherein Rxe2x80x2a and Rxe2x80x3a, which may be the same or different, may take any of the values of Ra and may also form, together with the nitrogen atom carrying them, a 5- to 10-membered cyclic group which may contain, in addition to the nitrogen atom by which it is linked, from one to three hetero atoms selected from oxygen, sulphur and nitrogen, and R1a may take any of the values of Ra except for the hydrogen atom),
a group of formula (VI): 
xe2x80x83wherein
R2 represents a group Ra as defined hereinbefore,
R3 represents a group CORxe2x80x2a, CSRxe2x80x2a, CONRxe2x80x2aRxe2x80x3a, CSNRxe2x80x2aRxe2x80x3a, COORxe2x80x2a, CSORxe2x80x2a or S(O)vRxe2x80x2a (wherein Rxe2x80x2a and Rxe2x80x3a, which may be the same or different, are as defined hereinbefore and may also form, together with the nitrogen atom carrying them, a cyclic group as defined hereinbefore, and v is 1 or 2),
a group of formula (VII): 
wherein v is as defined hereinbefore and R4 represents a group NRxe2x80x2aRxe2x80x3a, NRaCORxe2x80x2a, NRaCSRxe2x80x2a, NRaCONRxe2x80x2aRxe2x80x3a, NRaCSNRxe2x80x2aRxe2x80x3a or NRaCOORxe2x80x2a, wherein Ra, Rxe2x80x2a and Rxe2x80x3a are as defined hereinbefore,
or, when A represents a ring system of formula (II) or (III) or a biphenyl group, forms, together with two adjacent carbon atoms of the ring structure A carrying it,
a ring of formula (VIII): 
wherein E represents a group 
xe2x80x83wherein r, Q, Ra, Rxe2x80x2a and v are as defined hereinbefore,
the ring formed containing from 5 to 7 atoms and it being possible for the ring to contain from 1 to 3 hetero atoms selected from nitrogen, sulphur and oxygen, and one or more as unsaturations, and being optionally substituted by one or more radicals, which may be the same or different, selected from Ra, ORa, CORa, COORa, OCORa, NRxe2x80x2aRxe2x80x3a, NRaCORxe2x80x2a, CONRxe2x80x2aRxe2x80x3a, cyano, oxo, SRa, S(O)Ra, SO2Ra, CSRa, NRaCSRxe2x80x2a, CSNRxe2x80x2aRxe2x80x3a, NRaCONRxe2x80x2aRxe2x80x3a, NRaCSNRxe2x80x2aRxe2x80x3a and halogen atoms,
herein Ra, Rxe2x80x2a and Rxe2x80x3a, which may be the same or different, are as defined hereinbefore and Rxe2x80x2a and Rxe2x80x3a may also form, together with the nitrogen atom carrying them, a cyclic group as defined hereinbefore,
and Rxe2x80x2 represents a group of formula (IX):
xe2x80x94Gxe2x80x94R5xe2x80x83xe2x80x83(IX)
xe2x80x83wherein
G represents an alkylene chain xe2x80x94(CH2)txe2x80x94 (wherein t is an integer such that 0xe2x89xa6txe2x89xa64 when A represents a tricyclic structure and such that 1xe2x89xa6txe2x89xa64 when A represents a bicyclic structure), optionally substituted by one or more radicals, which may be the same or different, selected from Ra, ORa, COORa, CORa (in which Ra is as defined hereinbefore) or halogen atoms,
and R5 represents a group 
xe2x80x83wherein Q, Ra, Rxe2x80x2a and Rxe2x80x3a (which may be the same or different) are as defined hereinbefore, it being possible for Rxe2x80x2a and Rxe2x80x3a to form, together with the nitrogen atom carrying them, a cyclic group as defined hereinbefore,
it being understood that:
xe2x80x9cheterocycloalkylxe2x80x9d is taken to mean any saturated mono- or poly-cyclic group containing from 5 to 10 atoms containing from 1 to 3 hetero atoms selected from nitrogen, oxygen and sulphur,
xe2x80x9cheterocycloalkenylxe2x80x9d is taken to mean any non-aromatic mono- or poly-cyclic group containing one or more unsaturations, containing from 5 to 10 atoms and which may contain from 1 to 3 hetero atoms selected from nitrogen, oxygen and sulphur,
the term xe2x80x9csubstitutedxe2x80x9d used in respect of the expressions xe2x80x9calkylxe2x80x9d, xe2x80x9calkenylxe2x80x9d and xe2x80x9calkynylxe2x80x9d indicates that the groups in question are substituted by one or more radicals, which may be the same or different, selected from hydroxy, linear or branched (C1-C6)alkoxy, linear or branched (C1-C6)alkyl, linear or branched (C1-C6)polyhaloalkyl, amino and halogen atoms,
the term xe2x80x9csubstitutedxe2x80x9d used in respect of the expressions xe2x80x9ccycloalkylxe2x80x9d, xe2x80x9ccycloalkylalkylxe2x80x9d, xe2x80x9ccycloalkenylxe2x80x9d, xe2x80x9ccycloalkenylalkyl xe2x80x9d, xe2x80x9cheterocycloalkylxe2x80x9d, xe2x80x9cheterocycloalkenylxe2x80x9d, xe2x80x9cheterocycloalkylalkylxe2x80x9d and xe2x80x9cheterocycloalkenylalkylxe2x80x9d indicates that the cyclic moiety of the groups in question is substituted by one or more radicals, which may be the same or different, selected from hydroxy, linear or branched (C1-C6)alkoxy, linear or branched (C1-C6)alkyl, linear or branched (C1-C6)polyhaloalkyl, amino and halogen atoms,
xe2x80x9carylxe2x80x9d is taken to mean any aromatic, mono- or poly-cyclic group containing from 6 to 22 carbon atoms, and also the biphenyl group,
xe2x80x9cheteroarylxe2x80x9d is taken to mean any aromatic mono- or poly-cyclic group containing from 5 to 10 atoms containing from 1 to 3 hetero atoms selected from nitrogen, oxygen and sulphur,
it being possible for the xe2x80x9carylxe2x80x9d and xe2x80x9cheteroarylxe2x80x9d groups to be substituted by one or more radicals, which may be the same or different, selected from hydroxy, linear or branched (C1-C6)alkoxy, linear or branched (C1-C6)alkyl, linear or branched (C1-C6)polyhaloalkyl, cyano, carboxy, nitro, amino and halogen atoms,
to it being understood that:
when A represents an indole nucleus, there cannot be any substituents in the 2-position,
when A represents an indole nucleus and R represents a group xe2x80x94NHCORxe2x80x2a, xe2x80x94NHCOORxe2x80x2a or NHCONRxe2x80x2aRxe2x80x3a, then Gxe2x80x94R5 cannot represent a group xe2x80x94(CH2)2xe2x80x94NHCORb wherein Rb represents a (C1-C4)alkyl or CF3 group,
when A represents a benzofuran or benzothiophene nucleus, there cannot be any COPh groups (wherein Ph is substituted or unsubstituted) in the 2-position,
when A represents a benzofuran or benzothiophene nucleus, R cannot represent a group xe2x80x94NRaCORc, xe2x80x94NHSO2Rc, xe2x80x94NHCOCH2Rc, or NHCONHRc wherein Rc represents a heterocyclic or aryl group,
when A represents a tetrahydronaphthalene group, R5 cannot represent a group CONRxe2x80x2aRxe2x80x3a,
when A represents a hydrocarbon ring system and R5 represents a group NHCORxe2x80x2a, then R cannot represent a group COORxe2x80x2a,
the compound of formula (I) cannot represent:
N-{8-[(acetylamino)methyl]-2-naphthyl}-2-methylpropanamide,
N-(2-{5-[(4-ethoxyanilino)sulphonyl]-1H-indol-3-yl}ethyl)acetamide,
8-[(acetylamino)methyl]-N-isopropyl-2-naphthamide,
their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
Among the pharmaceutically acceptable acids there may mentioned, without implying any limitation, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, methanesulphonic acid, camphoric acid, oxalic acid etc.
Among the pharmaceutically acceptable bases there may mentioned, without implying any limitation, sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine etc.
Preferred compounds of the invention are those wherein A represents a ring system of formula (IIxe2x80x2): 
wherein B, X and symbol . . . are as defined hereinbefore, or (IIIxe2x80x2): 
wherein B wherein Bxe2x80x2, Txe2x80x2, Xxe2x80x2 and the symbol . . . are as defined hereinbefore.
The invention advantageously relates to compounds wherein A (unsubstituted or substituted by a single substituent (in addition to R and Rxe2x80x2) preferably in the 2-position (formula IIxe2x80x2) or in the 3-position (formula IIIxe2x80x2), represents a cyclic system of formula (IIxe2x80x2): 
wherein B, X and the symbol . . . are as defined hereinbefore, such as, for example, (dihydro)benzothiophene, (dihydro)benzofuran, indole, indoline, indan, indene, azaindole, thienopyridine or furopyridine, or of formula (IIIxe2x80x2): 
wherein Bxe2x80x2, Txe2x80x2, Xxe2x80x2 and the symbol . . . are as defined hereinbefore, such as, for example, naphthalene, tetrahydronaphthalene, (thio)chroman, (dihydro)benzodioxin, (dihydro)benzoxathiin, (dihydro)benzochromene.
Even more advantageously, the invention relates to compounds wherein A of formula (IIxe2x80x2) or (IIIxe2x80x2) is substituted by R in the 5-position (formula IIxe2x80x2)or 7-position (formula IIIxe2x80x2) and by Rxe2x80x2 in the 3-position (formula IIxe2x80x2) or 1- or 2-position (formula IIIxe2x80x2).
Preferred substituents R of the invention are those represented by a group of formula (V), (VI) or (VII).
More advantageously, preferred substituents R of the invention are those represented by a group of formula (V) wherein Q represents an oxygen atom and R1 represents a group NRxe2x80x2aRxe2x80x3a (wherein Rxe2x80x2a and Rxe2x80x3a are as defined hereinbefore) or OR1a (wherein R1a is as defined hereinbefore), a group of formula (VI) wherein R3 represents a group CORxe2x80x2a or COORxe2x80x2a (wherein Rxe2x80x2a is as defined hereinbefore), or a group of formula (VII) wherein v is 2 and R4 represents a group NRxe2x80x2aRxe2x80x3a as defined hereinbefore.
Even more advantageously, preferred substituents R of the invention are those represented by a group CONRxe2x80x2aRxe2x80x3a or SO2NRxe2x80x2aRxe2x80x3a wherein Rxe2x80x2a and Rxe2x80x3a, which may be the same or different, represent a hydrogen atom or an alkyl, polyhaloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl group, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, trifluoromethyl, vinyl, allyl, propargyl, phenyl, naphthyl, benzyl, phenethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, methylcyclopropyl, ethylcyclopropyl, furyl, thienyl, pyridyl, furylmethyl, pyridylmethyl, or form, together with the nitrogen atom carrying them, a piperazine, piperidine, morpholine or thiomorpholine group, or by a group NCORxe2x80x2a, NCOORxe2x80x2a or COOR1a wherein Rxe2x80x2a represents a hydrogen atom, an alkyl, polyhaloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl group, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, trifluoromethyl, vinyl, allyl, propargyl, phenyl, naphthyl, benzyl, phenethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, methylcyclopropyl, ethylcyclopropyl, furyl, thienyl, pyridyl, furylmethyl, pyridylmethyl, and R1a represents an alkyl, polyhaloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl group, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, trifluoromethyl, vinyl, allyl, propargyl, phenyl, naphthyl, benzyl, phenethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, methylcyclopropyl, ethylcyclopropyl, furyl, thienyl, pyridyl, furylmethyl, pyridylmethyl.
Preferred substituents Rxe2x80x2 of the invention are those wherein G represents an unsubstituted or substituted alkylene chain xe2x80x94(CH2)txe2x80x94, wherein t is 2 or 3, and R5 represents a group 
wherein Ra, Rxe2x80x2a, Rxe2x80x3a and Q are as defined hereinbefore.
Even more advantageously, preferred substituents Rxe2x80x2 of the invention are those wherein G represents a group xe2x80x94(CH2)txe2x80x94, wherein t is 2 or 3, and R5 represents a group 
wherein Rxe2x80x2a represents an alkyl, polyhaloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloakylalkyl, cycloalkenylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl group, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, trifluoromethyl, vinyl, allyl, propargyl, phenyl, naphthyl, benzyl, phenethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, methylcyclopropyl, ethylcyclopropyl, furyl, thienyl, pyridyl, furylmethyl, pyridylmethyl, or G represents a group xe2x80x94(CH2)3xe2x80x94 and R5 represents a group 
wherein Ra represents an alkyl, polyhaloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloakylalkyl, cycloalkenylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl group, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, trifluoromethyl, vinyl, allyl, propargyl, phenyl, naphthyl, benzyl, phenethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, methylcyclopropyl, ethylcyclopropyl, furyl, thienyl, pyridyl, furylmethyl, pyridylmethyl.
More especially, preferred compounds of the invention are those wherein A represents a ring system of formula (IIxe2x80x2) or (IIIxe2x80x2) and R represents a group of formula (V), (VI) or (VII).
More advantageously, the invention relates to compounds wherein:
A represents a group of formula (IIxe2x80x2) or (IIIxe2x80x2) substituted in the 5-position (formula IIxe2x80x2) or 7-position (formula IIIxe2x80x2) by R and in the 3-position (formula IIxe2x80x2) or 1- or 2-position (formula IIIxe2x80x2) by Rxe2x80x2,
and R represents a group CONRxe2x80x2aRxe2x80x3a, SO2NRxe2x80x2aRxe2x80x3a, COOR1a, NHCORxe2x80x2a or NHCOORxe2x80x2a (wherein Rxe2x80x2a, Rxe2x80x3a and R1a are as defined hereinbefore).
Even more advantageously, preferred compounds of the invention are those wherein A represents a ring system of formula (IIxe2x80x2) or (IIIxe2x80x2) optionally substituted (in addition to R and Rxe2x80x2) by a substituent in the 2-position (formula IIxe2x80x2) or 3-position (formula IIIxe2x80x2), substituted in the 5-position (formula IIxe2x80x2) or 7-position (formula IIIxe2x80x2) by R and in the 3-position (formula IIxe2x80x2)or 1- or 2-position (formula IIIxe2x80x2) by Rxe2x80x2, R represents a group CONRxe2x80x2aRxe2x80x3a, SO2NRxe2x80x2aRxe2x80x3a, COOR1a, NHCORxe2x80x2a or NHCOORxe2x80x2a (wherein Rxe2x80x2a, Rxe2x80x3a and R1a are as defined hereinbefore), and Rxe2x80x2 is such that G represents an unsubstituted or substituted alkylene chain xe2x80x94(CH2)txe2x80x94, wherein t is 2 or 3, and R5 represents a group 
wherein Ra, Rxe2x80x2a, Rxe2x80x3a and Q are as defined hereinbefore.
Even more especially, the invention relates to (dihydro)benzothiophenes, (dihydro)benzofurans, indoles, indolines, indenes, indans, azaindoles, thieno- or furopyridines optionally substituted in the 2-position, and to dihydronaphthalenes, tetrahydronaphthalenes, naphthalenes or chromans optionally substituted in the 3-position, substituted in the 5-position (or 7-position, respectively) by a group CONRxe2x80x2aRxe2x80x3a, SO2NRxe2x80x2aRxe2x80x3a, COOR1a, NHCORxe2x80x2a or NHCOORxe2x80x2a wherein Rxe2x80x2a and Rxe2x80x3a, which may be the same or different, represent a hydrogen atom, an alkyl, polyhaloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloakylalkyl, cycloalkenylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl group, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, trifluoromethyl, vinyl, allyl, propargyl, phenyl, naphthyl, benzyl, phenethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, methylcyclopropyl, ethylcyclopropyl, furyl, thienyl, pyridyl, furylmethyl, pyridylmethyl, or Rxe2x80x2a and Rxe2x80x3a form, together with the nitrogen atom carrying them, a piperazine, piperidine, morpholine or thiomorpholine group, and R1a represents an alkyl, polyhaloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloakylalkyl, cycloalkenylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl group, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, trifluoromethyl, vinyl, allyl, propargyl, phenyl, naphthyl, benzyl, phenethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, methylcyclopropyl, ethylcyclopropyl, furyl, thienyl, pyridyl, furylmethyl, pyridylmethyl, and substituted in the 3-position (or 1 - or 2-position, respectively) by a group xe2x80x94(CH2)txe2x80x94NHCORxe2x80x2a wherein t is 2 or 3 and Rxe2x80x2a represents an alkyl, polyhaloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloakylalkyl, cycloalkenylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl group, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, trifluoromethyl, vinyl, allyl, propargyl, phenyl, naphthyl, benzyl, phenethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, methylcyclopropyl, ethylcyclopropyl, furyl, thienyl, pyridyl, furylmethyl, pyridylmethyl.
Even more advantageously, preferred compounds of the invention are: naphthalenes, dihydronaphthalenes or tetrahydronaphthalenes optionally substituted in the 3-postion, substituted in the 7-position by a group NHCORa, NHCOORa, CONHRa or COOR1a (wherein Ra and R1a are as defined hereinbefore) and substituted in the 1-position by a group xe2x80x94(CH2)txe2x80x94NHCORxe2x80x2a wherein t is 2 or 3 and Rxe2x80x2a is as defined hereinbefore, or benzofurans or benzothiophenes optionally substituted in the 2-position, substituted in the 5-position by a group NHCORa, NHCOORa, CONHRa or COOR1a (wherein Ra and R1a are as defined hereinbefore) and substituted in the 3-position by a group xe2x80x94(CH2)txe2x80x94NHCORxe2x80x2a wherein t is 2 or 3 and Rxe2x80x2a is as defined hereinbefore.
The invention relates very particularly to the compounds of formula (I) that are:
N-{2-[6-(acetylamino)-2,3-dihydro-1H-1 -indenyl]ethyl}acetamide,
methyl 3-[2-(2-furoylamino)ethyl]-1-benzofuran-5-carboxylate,
methyl 3-{2-[(cyclopentylcarbonyl)amino]ethyl}-1-benzofuran-5-carboxylate,
methyl 3-{2-[(cyclopropylcarbonyl)amino]ethyl}-1-benzofuran-5-carboxylate,
methyl 3-[2-(3-butenoylamino)ethyl]-1-benzofuran-5-carboxylate,
N,N-diphenyl-3-[3-(acetylamino)propyl]benzo[b]furan-5-carboxamide,
3-[2-(acetylamino)ethyl]-1-benzofuran-5-carboxamide,
3-{2-[(cyclopropylcarbonyl)amino]ethyl}-1-benzofuran-5-carboxamide,
3-[2-(2-furoylamino)ethyl]-1-benzofuran-5-carboxamide,
3-{2-[(cyclopropylcarbonyl)amino]ethyl}-N-methyl-1-benzofuran-5-carboxamide,
3-[2-(acetylamino)ethyl]-N-methyl-1-benzofuran-5-carboxamide,
3-{2-[(cyclopentylcarbonyl)amino]ethyl}-N-methyl-1-benzofuran-5-carboxamide,
3-[2-(benzoylamino)ethyl]-N-methyl-1-benzofuran-5-carboxamide,
3-{2-[(cyclopropylcarbonyl)amino]ethyl}-N-methyl-1-benzofuran-5-carboxamide,
3-[2-(benzoylamino)ethyl]-N-methyl-1-benzofuran-5-carboxamide,
3-[2-(acetylamino)ethyl]-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide,
N-isopropyl-N-(2-propynyl)-3-[(acetylamino)methyl]-2-benzylbenzo[b]thiophene-5-carboxamide,
N-{3-[2-(acetylamino)ethyl]-1-benzofuran-5-yl}-2,2,2-trifluoroacetamide,
N-{2-[5-(acetylamino)-1-benzofuran-3-yl]ethyl}cyclopropanecarboxamide,
N-{2-[5-(acetylamino)-1-benzothiophen-3-yl]ethyl}benzamide,
N-{8-[2-([2-phenylacetyl]amino)ethyl]-2-naphthyl}butanamide,
N-(8-{2-[(2-bromoacetyl)amino]ethyl}-2-naphthyl)-1-cyclohexanecarboxamide,
N-{8-[2-(heptanoylamino)ethyl]-2,6-dinaphthyl}-2-butenamide,
N-{8-[2-(acetylamino)ethyl]-2-naphthyl}acetamide,
N-ethyl-8-{2-[(2-phenylacetyl)amino]ethyl}-2-naphthamide,
N,N-diethyl-8-{2-[2-[(cyclopropylmethyl)amino]-2-oxoethyl}-2-naphthamide,
N-phenyl-8-(2-{methyl[(propylamino)carbonyl]amino}ethyl)-2-naphthamide,
N-benzyl-1-{2-[(2,2,2-trifluoroacetyl)amino]ethyl}-2-naphthamide,
N-(2-{7-[(methylamino)carbonyl]-1-naphthyl}ethyl)-2-furamide,
N-{2-[7-(aminosulphonyl)-1-naphthyl]ethyl}acetamide,
N-(2-{7-[(methylamino)sulphonyl]-1-naphthyl}ethyl)acetamide,
N-(2-{7-[(methylamino)sulphonyl]-1-naphthyl}ethyl)-2-furamide,
N-(2-{(7-[(ethylamino)sulphonyl]-1-naphthyl}ethyl) benzamide,
N-(2-{7-[(methylamino)sulphonyl]-1-naphthyl}ethyl)cyclopropanecarboxamide,
N-(3-{5-[(methylamino)sulphonyl]-1-benzofuran-3-yl}propyl)acetamide,
N-(2-{5-[(propylamino)sulphonyl]-1-benzofuran-3-yl}ethyl)acetamide,
N-(2-{5-[(cyclopropylamino)sulphonyl]-1-benzofuran-3-yl}ethyl)benzamide,
N-(2-{5-[(methylamino)sulphonyl]-1-benzofuran-3-yl}ethyl)-2-furamide,
N-(2-{5-[(methylamino)sulphonyl]-1-benzofuran-3-yl}ethyl)cyclopropanecarboxamide,
N-(2-{(2-benzyl-5-[(methylamino)sulphonyl]-1-benzothiophen-3-yl}ethyl)acetamide,
N-(2-{5-[(isopropylamino)sulphonyl]-1-benzothiophen-3-yl}ethyl)cyclopropanecarboxamide,
N-(2-{5-[(methylamino)sulphonyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl)acetamide,
N-(2-{5-[(methylamino)sulphonyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl)cyclopropanecarboxamide,
N-(2-{5-[(methylamino)sulphonyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl)benzamide,
N-(2-{5-[(methylamino)sulphonyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl)-2-furamide,
methyl N-{3-[2-(acetylamino)ethyl]benzo[b]furan-5-yl}carbamate,
methyl 3-{2-[(cyclopropylcarbonyl)amino]ethyl}-1-benzofuran-5-yl-carbamate,
tert-butyl 3-[2-(acetylamino)ethyl]-1-benzofuran-5-yl-carbamate,
tert-butyl 3-[2-(acetylamino)ethyl]-1-benzofuran-5-yl-(methyl)carbamate,
methyl 3-[2-(benzoylamino)ethyl]-1-benzofuran-5-yl-carbamate,
methyl 3-[2-(isobutyrylamino)ethyl]-1-benzofuran-5-yl-carbamate,
methyl 5-[(acetylamino)methyl]-2,3-dihydro-1,4-benzodioxin-6-yl-carbamate,
methyl 3-[(acetylamino)methyl]-3,4-dihydro-2H-chromen-6-yl-carbamate,
ethyl 3-[2-(acetylamino)ethyl]-2,3-dihydro-]-1H-inden-5-yl-carbamate,
methyl 3-[2-(acetylamino)ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl-carbamate,
methyl 3-[2-(2-furoylamino)ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl-carbamate,
methyl 3-[2-(benzoylamino)ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl-carbamate,
methyl 3-{2-[(cyclopropylcarbonyl)amino]ethyl}-1H-pyrrolo[2,3-b]pyridin-5-yl-carbamate,
ethyl N-(8-{2-[(2-bromoacetyl)amino]ethyl}-2-naphthyl)carbamate,
methyl N-{8-[2-(acetylamino)ethyl]-6-phenyl-2-naphthyl}carbamate,
hexyl N-{8-[2-(acetylamino)ethyl]-5,6,7,8-tetrahydro-2-naphthyl}carbamate,
methyl 8-[2-(acetylamino)ethyl]-2-naphthyl-carbamate,
methyl 3-[2-(2-furoylamino)ethyl]-1-benzofuran-5-yl-carbamate,
methyl 3-{2-[(cyclopentylcarbonyl)amino]ethyl}-1-benzofuran-5-yl-carbamate,
methyl 3-[2-(benzoylamino)ethyl]-1-benzofuran-5-carboxylate,
methyl 3-[2-(isobutylamino)ethyl]-1-benzofuran-5-carboxylate,
3-[2-(benzoylamino)ethyl]-1-benzofuran-5-carboxamide.
The enantiomers and diastereoisomers, as well as the addition salts with a pharmaceutically acceptable acid or base, of the preferred compounds of the invention form an integral part of the invention.
The invention relates also to a process for the preparation of compounds of formula (I), which process is characterised in that there is used as starting material the compound of formula (X): 
wherein A and Rxe2x80x2 are as defined hereinbefore, which is subjected to demethylation using conventional agents such as HBr, AlCl3, AlBr3, BBr3 or Lewis acid/nucleophile binary systems such as AlCl3/PhCH2SH, or BBr3/Me2S, for example, to obtain the compound of formula (XI):
HOxe2x80x94Axe2x80x94Rxe2x80x2xe2x80x83xe2x80x83(XI)
wherein A and Rxe2x80x2 are as defined hereinbefore,
which is converted, by means of the action of reagents such as POCl3, PCl5, Ph3PBr2, PhPCl4, HBr or HI, into the corresponding halogenated compound of formula (XII):
Hal-Axe2x80x94Rxe2x80x2xe2x80x83xe2x80x83(XII)
wherein A and Rxe2x80x2 are as defined hereinbefore and Hal represents a halogen atom (which compounds of formula (XII) can be obtained by exchange reactions such as, for example, the treatment of a chlorinated compound with KF in dimethylformamide to yield the corresponding fluorinated compound or the treatment of a brominated compound with KI in the presence of copper salts to yield the corresponding iodinated compound),
which is treated:
with carbon monoxide and Bu3SnH, the reaction being catalysed with palladium(0), to yield the corresponding aldehyde of formula (XIII): 
wherein A and Rxe2x80x2 are as defined hereinbefore,
which compound of formula (XIII) may alternatively be obtained by customary lithiation methods starting from the halogenated compound of formula (XII), or via the corresponding vinyl compound (obtained starting from the compound of formula (XII) by the action of vinyltributyltin and tetrakis palladium) subjected to ozonolysis, or furthermore by direct formylation of the nucleus A, for example according to a Vilsmeier reaction,
which compound of formula (XIII) is subjected to an oxidising agent to obtain the compound of formula (XIV):
HOOCxe2x80x94Axe2x80x94Rxe2x80x2xe2x80x83xe2x80x83(XIV)
wherein A and Rxe2x80x2 are as defined hereinbefore, which is:
either subjected, in the presence of an acid catalyst, to the action of an alcohol of formula R1aOH, wherein R1a is as defined hereinbefore, to yield the compound of formula (I/a), a particular case of the compounds of formula (I): 
wherein A, R1a and Rxe2x80x2 are as defined hereinbefore,
which may be subjected to a thionating agent, such as Lawesson""s reagent, for example, to yield the compound of formula (I/b), a particular case of the compounds of formula (I): 
wherein A, R1a and Rxe2x80x2 are as defined hereinbefore,
or converted, after the action of thionyl chloride and an azide, and then of an acid, into the compound of formula (XV):
H2Nxe2x80x94Axe2x80x94Rxe2x80x2xe2x80x83xe2x80x83(XV)
wherein A and Rxe2x80x2 are as defined hereinbefore, with which there is condensed:
either an acyl chloride ClCORa or the corresponding anhydride (mixed or symmetrical), wherein Ra is as defined hereinbefore, to yield the compound of formula (I/c), a particular case of the compounds of formula (I): 
wherein Ra, A and Rxe2x80x2 are as defined hereinbefore,
which may be subjected to the action of a compound of formula (XVI):
R1axe2x80x94Jxe2x80x83xe2x80x83(XVI)
wherein Rxe2x80x2a is as defined hereinbefore and J represents a leaving group such as a halogen atom or a tosyl group,
to obtain the compound of formula (I/d), a particular case of the compounds of formula (I): 
wherein Ra, R1a, A and Rxe2x80x2 are as defined hereinbefore,
which compounds of formulae (I/c) and (I/d) constitute the compound of formula (I/e), a particular case of the compounds of formula (I): 
wherein Ra, Rxe2x80x2a, A and Rxe2x80x2 are as defined hereinbefore,
which compound of formula (I/e) may be subjected to a thionating agent, such as Lawesson""s reagent, for example, to obtain the compound of formula (I/f), a particular case of the compounds of formula (I): 
wherein Ra, Rxe2x80x2a, A and Rxe2x80x2 are as defined hereinbefore,
or a compound of formula (XVII):
Qxe2x95x90Cxe2x95x90Nxe2x80x94Rxe2x80x2axe2x80x83xe2x80x83(XVII)
wherein Q and Rxe2x80x2a are as defined hereinbefore,
to yield the compound of formula (I/g), a particular case of the compounds of formula (I): 
wherein Rxe2x80x2a, Q, A and Rxe2x80x2 are as defined hereinbefore,
which may be subjected to the action of a compound of formula (XVI) to obtain the compound of formula (I/h), a particular case of the compounds of formula (I): 
wherein Q, R1a, A and Rxe2x80x2 are as defined hereinbefore and R2a and Rxe2x80x22a, which may be the same or different, may take any of the values of Ra except for the hydrogen atom and cannot form a cyclic structure together with the nitrogen atom carrying them,
or a compound of formula (XVIII): 
wherein Rxe2x80x2a is as defined hereinbefore, or its corresponding anhydride (Rxe2x80x2aOCO)2O,
to obtain the compound of formula (I/i), a particular case of the compounds of formula (I): 
wherein Rxe2x80x2a, A et Rxe2x80x2 are as defined hereinbefore,
which may be subjected to the action of a compound of formula (XVI) and/or the action of a thionating agent to yield the compound of formula (I/j), a particular case of the compounds of formula (I): 
wherein Ra, Rxe2x80x2a, Q, A and Rxe2x80x2 are as defined hereinbefore,
or a compound of formula (XIX):
RaSO2Clxe2x80x83xe2x80x83(XIX)
wherein Ra is as defined hereinbefore,
optionally followed by the action of a compound of formula (XVI) to yield the compound of formula (I/k), a particular case of the compounds of formula (I): 
wherein Ra, A and Rxe2x80x2 are as defined hereinbefore,
or which compound of formula (XI) is converted, by means of the action of benzylthiol and trifluoromethanesulphonic acid, into the corresponding benzylthio compound of formula (XX):
Phxe2x80x94CH2xe2x80x94Sxe2x80x94Axe2x80x94Rxe2x80x2xe2x80x83xe2x80x83(XX)
wherein A and Rxe2x80x2 are as defined hereinbefore,
which is placed in the presence of iodosobenzene and hydrochloric acid to yield the compound of formula (XXI):
ClSO2xe2x80x94Axe2x80x94Rxe2x80x2xe2x80x83xe2x80x83(XXI)
wherein A and Rxe2x80x2 are as defined hereinbefore,
with which there is condensed an amine Rxe2x80x2aRxe2x80x3aNH (wherein Rxe2x80x2a and Rxe2x80x3a are as defined hereinbefore),
to obtain the compound of formula (I/l), a particular case of the compounds of formula (I):
Rxe2x80x2aRxe2x80x3aNSO2xe2x80x94Axe2x80x94Rxe2x80x2xe2x80x83xe2x80x83(I/l)
wherein Rxe2x80x2a, Rxe2x80x3a, A and Rxe2x80x2 are as defined hereinbefore,
it being possible for the compound of formula (I/la), a particular case of the compounds of formula (I/l):
H2NSO2xe2x80x94Axe2x80x94Rxe2x80x2xe2x80x83xe2x80x83(I/la)
wherein A and Rxe2x80x2 are as defined hereinbefore, to be subjected to the action
of an acyl chloride ClCORxe2x80x2a, optionally followed by the action of a compound of formula (XVI) and/or Lawesson""s reagent,
to yield the compound of formula (I/m), a particular case of the compounds of formula (I): 
wherein Ra, Rxe2x80x2a, Q, A and Rxe2x80x2 are as defined hereinbefore,
of a compound of formula (XVII), optionally followed by the action of a compound of formula (XVI) to obtain the compound of formula (I/n), a particular case of the compounds of formula (I): 
wherein Ra, Rxe2x80x2a, Rxe2x80x3a, Q, A and Rxe2x80x2 are as defined hereinbefore,
or of a compound of formula (XVIII), optionally followed by the action of a compound of formula (XVI),
to yield the compound of formula (I/o), a particular case of the compounds of formula (I): 
wherein Ra, Rxe2x80x2a, A and Rxe2x80x2 are as defined hereinbefore,
which compounds (I/a) to (I/o) can be purified in accordance with a conventional separation technique, are converted, if desired, into their addition salts with a pharmaceutically acceptable acid or base and, optionally, are separated into their isomers in accordance with a conventional separation technique.
The starting compounds (X) are either commercially available or are described in the literature, for example in the Patent Applications EP0447285, EP0527687, EP0562956, EP0591057, EP0662471, EP0745586, EP0709371, EP0745583, EP0721938, EP0745584, EP0737670, EP0737685, or WO9738682.
Another advantageous process of the invention relating to preparation of the compounds of formula (I) is characterised in that there is used as starting material the compound of formula (XXII): 
wherein R and the symbol . . . are as defined hereinbefore, Yxe2x80x3 represents a group C(H)q (wherein q is 0, 1 or 2) or a bond, and Xxe2x80x3 represents an oxygen, nitrogen or sulphur atom or a group C(H)q (wherein q is 0, 1 or 2) or NR0 (wherein R0 is as defined hereinbefore), it being understood that when Xxe2x80x3 represents a nitrogen atom or a group NR0 then Yxe2x80x3 represents a bond,
which is subjected to a Wittig reaction and then to reduction to yield the compound of formula (XXIII): 
wherein R, Xxe2x80x3, Yxe2x80x3, G and the symbol . . . are as defined hereinbefore,
which may be oxidised to yield the compound of formula (XXIV): 
wherein R1, Xxe2x80x3, Yxe2x80x3, G and the symbol . . . are as defined hereinbefore,
which is:
either hydrolysed in an acid or basic medium and then subjected, after activation to the acid chloride form or in the presence of a coupling agent, to the action of an amine HNRxe2x80x2aRxe2x80x3a wherein Rxe2x80x2a and Rxe2x80x3a are as defined hereinbefore to yield the compound of formula (I/p), a particular case of the compounds of formula (I): 
wherein R, Xxe2x80x3, Yxe2x80x3, G, Rxe2x80x2a, Rxe2x80x3a and the symbol . . . are as defined hereinbefore,
which may be subjected to a thionating agent such as Lawesson""s reagent to yield the compound of formula (I/q), a particular case of the compounds of formula (1): 
wherein R, Xxe2x80x3, Yxe2x80x3, G, Rxe2x80x2a, Rxe2x80x3a and the symbol . . . are as defined hereinbefore,
or hydrolysed in an acid or basic medium and then converted into the corresponding azide to yield, after having been subjected to a Curtius rearrangement and hydrolysis, the compound of formula (XXV): 
wherein R, Xxe2x80x3, Yxe2x80x3 and G are as defined hereinbefore,
which is reacted with:
an acyl chloride ClCORxe2x80x2a or the corresponding anhydride (mixed or symmetrical) wherein Rxe2x80x2a is as defined hereinbefore, optionally followed by the action of a compound of formula (XVI) and/or the action of a thionating agent to yield the compound of formula (I/r), a particular case of the compounds of formula (I): 
wherein R, Xxe2x80x3, Yxe2x80x3, G, Ra, Rxe2x80x2a, Q and the symbol . . . are as defined hereinbefore,
or with a compound of formula (XVII), optionally followed by the action of a compound of formula (XVI) to yield the compound of formula (I/s), a particular case of the compounds of formula (I): 
wherein R, Xxe2x80x3, Yxe2x80x3, G, Ra, Rxe2x80x2a, Rxe2x80x3a, Q and the symbol . . . are as defined hereinbefore,
which compounds (I/p) to (I/s) can be purified in accordance with a conventional separation technique, are converted, if desired, into their addition salts with a pharmaceutically acceptable acid or base and, optionally, are separated into their isomers in accordance with a conventional separation technique.
The compounds of formula (XXII) are either commercially available or easily accessible to the person skilled in the art,
starting from the compound of formula (XXVI): 
wherein R is as defined hereinbefore and Xxe2x80x2xe2x80x3 represents an oxygen or sulphur atom or a group NR0 (wherein R0 is as defined hereinbefore),
(the compound of formula (XXVI) either being commercially available or being obtained starting from the compound of formula (XXVIxe2x80x2): 
wherein Xxe2x80x2xe2x80x3 is as defined hereinbefore, by conventional reactions for substitution of the aromatic nucleus),
which is subjected to the action of AlCl3 to yield the compound of formula (XXVII): 
wherein R and Xxe2x80x2xe2x80x3 are as defined hereinbefore,
which is subjected to bromination to obtain the compound of formula (XXVIII): 
wherein Xxe2x80x2xe2x80x3 and R are as defined hereinbefore,
which is placed in a basic medium to yield the compound of formula (XXIX), a particular case of the compounds of formula (XXII): 
wherein R and Xxe2x80x2xe2x80x3 are as defined hereinbefore,
or starting from the compound of formula (XXX): 
wherein R, Xxe2x80x3, Yxe2x80x3 and the symbol . . . are as defined hereinbefore,
which is cyclised in the presence of polyphosphoric acid to yield the compound of formula (XXII).
The invention relates also to a process for the preparation of compounds of formula (I) wherein R represents a ring of formula (VIII), which process is characterised in that compounds of formulae (I/a) to (I/s) are used as starting materials, which are cyclised according to methods described in the literature, for example in the Patent Applications EP0708099 or WO9732871.
The compounds of the invention and pharmaceutical compositions comprising them are proving to be useful in the treatment of disorders of the melatoninergic system.
Pharmacological study of the compounds of the invention has in fact shown them to be non-toxic, to have strong affinity for melatonin receptors and to possess important activities in respect of the central nervous system and, in particular, there have been found therapeutic properties in relation to sleep disorders, anxiolytic, antipsychotic and analgesic properties and in relation to the microcirculation, enabling it to be established that the products of the invention are useful in the treatment of stress, sleep disorders, anxiety, seasonal affective disorder, cardiovascular pathologies, pathologies of the digestive system, insomnia and fatigue resulting from jet lag, schizophrenia, panic attacks, melancholia, appetite disorders, obesity, insomnia, psychotic disorders, epilepsy, diabetes, Parkinson""s disease, senile dementia, various disorders associated with normal or pathological ageing, migraine, memory loss, Alzheimer""s disease, and also cerebral circulation disorders. In another field of activity, it appears that, in treatment, the products of the invention can be used in sexual dysfunction, that they have ovulation-inhibiting properties and immunomodulating properties and are able to be used in the treatment of cancers.
The compounds will preferably be used in the treatment of seasonal affective disorder, sleep disorders, cardiovascular pathologies, insomnia and fatigue resulting from jet lag, appetite disorders and obesity.
For example, the compounds will be used in the treatment of seasonal affective disorder and sleep disorders.
The present invention relates also to pharmaceutical compositions comprising at least one compound of formula (I), alone or in combination with one or more pharmaceutically acceptable excipients.
Among the pharmaceutical compositions according to the invention there may be mentioned more especially those that are suitable for oral, parenteral, nasal, per- or trans-cutaneous, rectal, perlingual, ocular or respiratory administration and especially tablets, dragees, sublingual tablets, sachets, paquets, gelatin capsules, glossettes, lozenges, suppositories, creams, ointments, dermal gels and drinkable or injectable ampoules.
The dosage varies according to the sex, age and weight of the patient, the route of administration, the nature of the therapeutic indication, or possible associated treatments, and ranges from 0.01 mg to 1 g per 24 hours in 1 or more administrations.
The following Examples illustrate the invention but do not limit it in any way. The following Preparations yield compounds of the invention or synthesis intermediates that are useful in preparation of the compounds of the invention.
Under an inert atmosphere, 27.5 mmol of boron tribromide/dimethyl sulphide complex are dissolved in 100 ml of dichloromethane and stirred for 15 min at ambient temperature. A solution of 13.7 mmol of N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide in 50 ml of dichloromethane is added and the reaction mixture is heated at reflux for 30 hours. After cooling, the reaction mixture is hydrolysed with caution and the dichloromethane is evaporated off. The mixture is then extracted with ethyl acetate, the combined organic phases are washed with a 1M aqueous solution of potassium bicarbonate and then with 1M sodium hydroxide solution. The organic phase is dried over magnesium sulphate and concentrated to yield the title compound.
The procedure is as in Preparation 1, but the N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide is replaced by N-[2-(7-methoxy-1-naphthyl)ethyl]-2-phenylacetamide.
In Preparations 3 to 37, the procedure is as in Preparation 1, but the N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide is replaced by the appropriate methoxylated starting substrate.
Chlorine (10 mmol) is bubbled into dichlorophenylphosphine at a flow rate such that the reaction temperature is maintained between 70 and 80xc2x0 C. After all the chlorine has been added, the phenylphosphine tetrachloride so obtained is a pale yellow liquid. 10 mmol of the product obtained in Preparation 5 are added all at once and the reaction mixture is heated at 160xc2x0 C. overnight. After cooling, the solution is poured into a water/ice mixture (20 ml) and is neutralised with a 50% aqueous solution of sodium hydroxide. After extraction with ether, the organic phases are dried and concentrated under reduced pressure to yield a residue, which is chromatographed on silica gel to obtain the pure title product.
In Preparation 39, the procedure is as in Preparation 38, but the appropriate starting compound is used.
Starting compound: Preparation 24
Triphenylphosphine (10 mmol) and acetonitrile (70 ml) are poured into a 150 ml three-necked flask equipped with a bromine funnel, a condenser surmounted by a tube filled with calcium chloride and a mechanical stirrer. The solution is cooled with the aid of an ice bath, with stirring, and bromine is added (10 mmol). At the end of the addition, the ice bath is removed and the product obtained in Preparation 2 (8 mmol) is then added. The reaction mixture is stirred at 60-70xc2x0 C. until the starting compound has disappeared (monitored by TLC). At the end of the reaction, the mixture is filtered and the filtrate is then concentrated under reduced pressure. The residue is taken up in ethyl acetate, washed with water and then with saturated potassium hydrogen carbonate solution and once again with water, and is then dried over magnesium sulphate and concentrated under reduced pressure. The residue is filtered through silica gel to yield the title product.
In Preparations 41 to 72.1, the procedure is as in Preparation 40, starting from the appropriate reactant.
Starting compound: Preparation 5
Starting compound: Preparation 7
Starting compound: Preparation 10
Starting compound: Preparation 11
Starting compound: Preparation 14
Starting compound: Preparation 16
Starting compound: Preparation 19
Starting compound: Preparation 22
Starting compound: Preparation 25
Starting compound: Preparation 26
Starting compound: Preparation 28
Starting compound: Preparation 29
Starting compound: Preparation 31
Starting compound: Preparation 32
Starting compound: Preparation 33
Starting compound: Preparation 34
Starting compound: Preparation 35
Starting compound: Preparation 1
Starting compound: Preparation 9
Starting compound: Preparation 3
Starting compound: Preparation 4
Starting compound: Preparation 8
Starting compound: Preparation 12
Starting compound: Preparation 15
Starting compound: Preparation 17
Starting compound: Preparation 20
Starting compound: Preparation 21
Starting compound: Preparation 23
Starting compound: Preparation 27
Starting compound: Preparation 37
Starting compound: Preparation 13
Starting compound: Preparation 18
Starting compound: Preparation 36
A mixture of the product obtained in Preparation 40 (2 mmol), potassium iodide (30 mmol) and copper(I) iodide (10 mmol) in hexamethylphosphoramide (6 ml) is heated at 150-160xc2x0 C., with stirring, under a nitrogen atmosphere until 90% conversion has been achieved (monitored by TLC). Then, dilute hydrochloric acid, and then ether, are added and the mixture is then filtered to remove the insoluble copper(I) salts. The organic phase is separated off, washed with sodium sulphite solution and with water, dried over magnesium sulphate and evaporated to yield a residue which is chromatographed on silica gel to yield the title product.
In Preparations 74 to 108 the procedure is as in Preparation 73, but the product of Preparation 40 is replaced by the appropriate substrate.
Starting compound: Preparation 41
Starting compound: Preparation 42
Starting compound: Preparation 43
Starting compound: Preparation 44
Starting compound: Preparation 45
Starting compound: Preparation 46
Starting compound: Preparation 47
Starting compound: Preparation 48
Starting compound: Preparation 39
Starting compound: Preparation 49
Starting compound: Preparation 50
Starting compound: Preparation 51
Starting compound: Preparation 52
Starting compound: Preparation 53
Starting compound: Preparation 54
Starting compound: Preparation 55
Starting compound: Preparation 56
Starting compound: Preparation 57
Starting compound: Preparation 58
Starting compound: Preparation 59
Starting compound: Preparation 60
Starting compound: Preparation 61
Starting compound: Preparation 38
Starting compound: Preparation 62
Starting compound: Preparation 63
Starting compound: Preparation 64
Starting compound: Preparation 65
Starting compound: Preparation 66
Starting compound: Preparation 67
Starting compound: Preparation 68
Starting compound: Preparation 69
Starting compound: Preparation 70
Starting compound: Preparation 71
Starting compound: Preparation 72.1
Starting compound: Preparation 72
Step A: N-[2-(7-Vinyl-1-naphthyl)ethyl]-2-phenylacetamide
15 mmol of the product obtained in Preparation 73, 16 mmol of vinyltributyltin and 0.43 mmol of tetrakis(triphenylphosphine)palladium are heated in 30 ml of N-methylpyrrolidinone at 110xc2x0 C. for 3 hours, with stirring. After evaporating off the solvent, the residue is taken up in 20 ml of dichloromethane and treated with 10% aqueous potassium fluoride solution. After extraction, concentration under reduced pressure and chromatography on silica gel, the pure title product is obtained.
Step B: N-[2-(7-Formyl-1-naphthyl)ethyl]-2-phenylacetamide
To a solution of 10 mmol of the product obtained in Step A in a mixture of 50 ml of dioxane and 25 ml of water there are added, at ambient temperature, 1.10 g of osmium tetroxide in 2-methyl-2-propanol and then 8.70 g of sodium periodate. After stirring overnight at ambient temperature, the suspension is filtered and the filtrate is concentrated under reduced pressure. The residue obtained is taken up in dichloromethane. The organic phase is washed with water, dried and evaporated. The residue is purified by chromatography on silica gel to yield the title product.
Step C: 8-{2-[(2-Phenylacetyl)amino]ethyl}-2-naphthoic acid
2.7 g of potassium permanganate in 50 ml of an acetone/water mixture (50/50) are added, at ambient temperature, to a solution of 6.88 mmol of the product obtained in Step B in 30 ml of acetone. The solution is stirred for 2 hours at ambient temperature and is then filtered. The filtrate is concentrated under reduced pressure and chromatographed on silica gel to yield the title product.
Step D: 8{-(2-[(2-Phenylacetyl)amino]ethyl}-2-naphthalenecarbonyl chloride
5 mmol of the product obtained in Step C are dissolved in 40 ml of thionyl chloride. After stirring under an inert atmosphere for 1 hour, the thionyl chloride is evaporated off under reduced pressure to yield the title product.
Step E: N-[2-(7-Amino-1-naphthyl)ethyl]-2-phenylacetamide
A solution of the product obtained in Step D (20 mmol) in dichloromethane (30 ml) containing tetrabutylammonium bromide (20 mg) is cooled in an ice bath. After adding sodium azide (24 mmol) dissolved in 5 ml of water, the solution is stirred vigorously at 0xc2x0 C. for 2 hours. The organic phase is separated off, washed with water (2xc3x975 ml) and dried over magnesium sulphate. After filtration, trifluoroacetic acid (30 mmol) is added and the solution is stirred under reflux for 60 hours. After cooling, the organic phase is washed with saturated sodium hydrogen carbonate solution (2xc3x975 ml) and is concentrated under reduced pressure. The residue is then taken up in methanol (20 ml); water (80 ml) and then potassium carbonate (30 mmol) are added. After stirring at ambient temperature for 20 hours, the reaction mixture is concentrated under reduced pressure to a volume of about 60 ml and is then extracted 3 times with ether (3xc3x9750 ml). After drying over sodium sulphate, the organic phase is filtered and then evaporated under reduced pressure. The residue is chromatographed on silica gel to yield the title product.
In Preparations 110 to 134 the procedure is as in Example 109, starting from the appropriate substrate.
Starting compound: Preparation 94
Starting compound: Preparation 95
Starting compound: Preparation 96
Starting compound: Preparation 97
Starting compound: Preparation 98
Starting compound: Preparation 78
Starting compound: Preparation 93
Starting compound: Preparation 92
Starting compound: Preparation 99
Starting compound: Preparation 100
Starting compound: Preparation 101
Starting compound: Preparation 102
Starting compound: Preparation 81
Starting compound: Preparation 103
Starting compound: Preparation 82
Starting compound: Preparation 104
Starting compound: Preparation 87
Starting compound: Preparation 88
Starting compound: Preparation 89
Starting compound: Preparation 106
Starting compound: Preparation 90
Starting compound: Preparation 91
Starting compound: Preparation 108
Starting compound: Preparation 107
Starting compound: Preparation 105
Preparations 135 to 145 are obtained by proceeding as in Preparation 1, starting from the appropriate substrate.
The procedure is as in Preparation 40, starting from the compound obtained in Preparation 142.
The procedure is as in Preparation 73, starting from the compound obtained in Preparation 146.
The procedure is as in Preparation 109, starting from the compound obtained in Preparation 147.
The procedure is as in Preparation 40, starting from the compound obtained in Preparation 145.
The procedure is as in Preparation 73, starting from the compound obtained in Preparation 149.
The procedure is as in Preparation 109, starting from the compound obtained in Preparation 150.
The procedure is as in Preparation 40, starting from the compound obtained in Preparation 144.
The procedure is as in Preparation 73, starting from the compound obtained in Preparation 152.
The procedure is as in Preparation 109, starting from the compound obtained in Preparation 153.
The procedure is as in Preparation 40, starting from the compound obtained in Preparation 143.
The procedure is as in Preparation 73, starting from the compound obtained in Preparation 155.
The procedure is as in Preparation 109, starting from the compound obtained in Preparation 156.
The procedure is as in Preparation 1.
The procedure is as in Preparation 40, starting from the compound obtained in Preparation 158.
The procedure is as in Preparation 73, starting from the compound obtained in Preparation 159.
The procedure is as in Preparation 109, starting from the compound obtained in Preparation 160.
The procedure is as in Preparation 1.
The procedure is as in Preparation 40, starting from the compound obtained in Preparation 162.
The procedure is as in Preparation 73, starting from the compound obtained in Preparation 163.
The procedure is as in Preparation 109, starting from the compound obtained in Preparation 164.
The procedure is as in Preparation 40, starting from the compound obtained in Preparation 140.
The procedure is as in Preparation 73, starting from the compound obtained in Preparation 166.
The procedure is as in Preparation 109, starting from the compound obtained in Preparation 167.
The procedure is as in Preparation 1.
The procedure is as in Preparation 40, starting from the compound obtained in Preparation 169.
The procedure is as in Preparation 73, starting from the compound obtained in Preparation 170.
The procedure is as in Preparation 109, starting from the compound obtained in Preparation 171.
The procedure is as in Preparation 40, starting from the compound obtained in Preparation 135.
The procedure is as in Preparation 73, starting from the compound obtained in Preparation 173.
The procedure is as in Preparation 40, starting from the compound obtained in Preparation 138.
The procedure is as in Preparation 73, starting from the compound obtained in Preparation 176.